Project Summary/Abstract Physical function decline in aging adults, which is a precursor to frailty, affects more than 60% of Americans older than 65 years of age, and leads to many adverse clinical outcomes. Because frailty requires intensive costly treatments, early interventions to promote physical function will reduce these adverse endpoints and their associated clinical outcomes and cost. To date, no studies have examined the molecular mechanisms involving demyelination and neurodegeneration as they relate to physical function decline, despite emerging evidence in demyelinating diseases such as multiple sclerosis linking them to mobility impairments. Long-term stability of the myelin sheath surrounding nerve cell axons depends on hydroxysphingolipids (SL[OH]s) produced by fatty acid 2-hydroxylase (FA2H). Mutations in the FA2H gene have been found to cause progressive gait impairments in children 2?6 years of age after an apparently normal development. Moreover, pathophysiological research in old mice without FA2H enzymatic activity suggests that the lack of SL(OH)s leads to late-onset demyelination and neurodegeneration. Our preliminary data from the Atherosclerosis Risk in Communities (ARIC) study determined that lower plasma levels of SM(OH)s, a family of SL(OH)s, were significantly associated with poorer physical function in a cross-sectional study of older adults. Therefore, SL(OH)s has considerable potential as plasma biomarkers of demyelination and neurodegeneration underlying physical function decline in older adults. Our central hypothesis is that lower plasma levels of SL(OH)s will be associated with poorer physical function and faster physical function decline over time in older adults. Logically built on our preliminary data, this proposal will examine all 3 major families of SL(OH)s in a cross-sectional study and a cohort study, and will be conducted by our experienced interdisciplinary team. We will apply an advanced, targeted lipidomics method to measure SL(OH)s in plasma of 400 ARIC participants collected at ARIC Visit 5 in 2011?2013 (our study baseline). We will use physical function evaluated at 2 time points, 5 years apart: Visit 5 (2011?2013) and Visit 6 (2016?2018) by 3 measures: grip strength; lower extremity physical function; and 4-meter walking speed. We will have 80% power to detect differences in 4-meter walking speed (our primary outcome) of 4.4 cm/s or greater per 1 standard deviation difference in values of an SL(OH) biomarker. The specific aims are: Aim 1) Determine the cross-sectional association of plasma SL(OH)s with physical function in older adults; and Aim 2) Evaluate the longitudinal relationship of plasma SL(OH)s with physical functional decline in older adults over time. Findings from our study will inform current biomarker studies of physical function in older adults and designs of future human intervention studies to boost physical function.